This invention relates to a novel group of diphenyl sulfamido compounds, processes for the preparation thereof, the use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 mediated diseases and pharmaceutical compositions for use in such therapy.
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2 or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al, Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatelila et al, J. Immunol. 148, 3216 (1992).
Groxcex1, GROxcex2, GROxcex3 and NAP-2 also belong to the chemokine xcex1 family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAxcex1, xcex2 and xcex3 respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, Groxcex1, GROxcex2, GROxcex3, NAP-2 and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, Groxcex1, GROxcex2, GROxcex3 and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al, Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, Strieter et al, Science 258, 1798 (1992).
In vitro, IL-8, Groxcex1, GROxcex2, GROxcex3, and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor, Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rxcex1, which binds only IL-8 with high affinity, and IL-8RB, which has high affinity for IL-8 as well as for GRO-xcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8xcex1 or xcex2 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8xcex1 or xcex2 receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein:
R is selected from the group consisting of OH, SH, and NHSO2Rd;
Rd is selected from the group consisting of NR6R7, alkyl, arylC1-4alkyl, arylC2-4 alkenyl, heteroaryl, hetroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, and heterocyclicC1-4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings are all unsubstituted or substituted;
R6 and R7 are, independently, hydrogen, or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, the ring being optionally substituted;
R1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, azide, (CR8R8)q S(O)tR4, hydroxy, hydroxy C1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, heteroaryl C1-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4R10, S(O)3H, S(O)3R8, (CR8R8)q C(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11(CR8R8)q C(O)OR12, (CR8R8)q OC(O) R11, (CR8R8)qNR4C(O)R11, (CR8R8)q NHS(O)2R17, (CR8R8)q and S(O)2NR4R5; or two R1 moieties together form Oxe2x80x94(CH2)sOxe2x80x94 or a 5 to 6 membered unsaturated ring;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, and heterocyclicC1-4 alkyl; or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which optionally comprises an additional heteroatom selected from oxygen, nitrogen and sulfur;
Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, azide, (CR8R8)q S(O)tR4, hydroxy, hydroxyC1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, arylC1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4R10, S(O)3H; S(O)3R8, (CR8R8)q C(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, C(O)R11, (CR8R8)q C(O)OR12, (CR8R8)q OC(O)R11, (CR8R8)q NR4C(O)R11, (CR8R8)q NHS(O)2Rd, and (CR8R8)q S(O)2NR4R5; or two Y moieties together form Oxe2x80x94(CH2)sOxe2x80x94 or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 5;
m is an integer having a value of 1 to 4;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is selected from the group consisting of hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl;
R12 is selected from the group consisting of hydrogen, C1-10 alkyl, optionally substituted aryl and optionally substituted arylalkyl; and
R17 is selected from the group consisting of C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings are all optionally substituted.
The compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8RA and RB receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo.
xe2x80x9cC2-5alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain moieties of 2 to 5 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
The term xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain moieties of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclicalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
The term xe2x80x9carylalkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
Preferred compounds of the present invention are selected from the group consisting of:
N-(4-Cyano-2-hydroxyphenyl)-Nxe2x80x2-(2-bromophenyl)-sulfamide;
N-(4-Cyano-2-hydroxyphenyl)-Nxe2x80x2-(2-chlorophenyl)-sulfamide;
N-(4-Cyano-2-hydroxyphenyl)-Nxe2x80x2-(2,3-dichlorophenyl)-sulfamide;
N-(4-Nitro-2-hydroxyphenyl)-Nxe2x80x2-(2-bromophenyl)-sulfamide; and
N-(4-Chloro-2-hydroxyphenyl)-Nxe2x80x2-(2-bromophenyl)-sulfamide.
The compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for producing compounds of Formula (I) having a variety of different R, R1, and aryl groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the guanidine nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with compounds only of Formula (I) this is merely for illustration purposes only. 
The desired aniline 6-scheme-1 can be prepared from the commercially available benzoxazolinone 1-scheme-1. Bromide 2-scheme-1 can be prepared from benzoxazolinone 1-scheme-1 using standard bromination conditions such as bromine and sodium acetate in acetic acid. Bromide 2-scheme-1 can be converted to the cyanide 3-scheme-1 using standard procedures such as copper (I) cyanide in refluxing DMF. The amide 3-scheme-1 can be converted to the BOC protected compound 4-scheme-1 using standard conditions such as BOC anhydride and triethylamine with a catalytic amount of dimethylaminopyridine in methylene chloride or another suitable organic solvent. The oxazolinone 4-scheme-1 can be converted to the desired aniline 6-scheme-1 by first hydrolysis to the phenol 5-scheme-1 using standard conditions such as potassium carbonate in methanol followed by removal of the BOC protecting group using standard conditions such as trifluoroacetic acid in methylene chloride or another suitable organic solvent to give the aniline 6-scheme-1. 
Alternatively, the desired substituted hydroxyaniline 4 can be prepared as outlined in Scheme 2. Commercially available substituted 3-chloroanilines 1 can be converted to the amide 2 using standard conditions well known in the art such as pivavolyl chloride and triethylamine in a suitable organic solvent such as methylene chloride. The amide 2 can be converted to the benzoxazole 3 using an excess amount of a strong base such as butyllithium in a suitable organic solvent such as THF under reduced reaction temperatures between xe2x88x9220 and xe2x88x9240xc2x0 C. followed by a protic workup. The desired phenolaniline 5 can be obtained from the benzoxazole 4 using standard hydrolysis conditions well known in the art such as sulfuric acid in water and heating at 85xc2x0 C. 
Compounds of structure 5 will be obtained from the readily prepared aniline 1 as outlined in scheme 3. Aniline 1 will be reacted with chlorosulfonic acid in chloroform or another suitable organic solvent to give the sulfonic acid 2. The sulfonic acid 2 will be converted to the sodium salt 3 using sodium carbonate or another suitable sodium base. The sodium salt 3 will be converted to the sulfonyl chloride 4 using standard techniques such as phosphorous chloride in phosphorous oxy chloride. The desired sulfoxamide 5 will be prepared by reacting sulfonyl chloride 4 with 2-bromoaniline in a suitable organic solvent such as DMF. The desired compound 6 will be obtained from the methoxy compound 5 using boron tribromide in methylene chloride or another suitable organic solvent.
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated.
In the Examples, all temperatures are in degrees Centigrade (xc2x0 C.). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. 1H-NMR (hereinafter xe2x80x9cNMRxe2x80x9d) spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.